dc.description.abstract
The influence of three different extrusion methods as well as extrusion
temperature and screw speed on drug release from PLGA-based implants were
investigated. Comparing biodegradable implants prepared with the Haake
MiniLab under extrusion parameters of 85 °C/ 30 rpm and 105 °C/ 120 rpm, an
increase in processing temperature and screw speed resulted in extrudates of
uneven surface with a so-called “sharkskin effect”. The increased surface area
led to a higher burst release of drug and ultimately resulted in a shorter release
phase due to an increased PLGA-degradation. Biodegradable implants prepared
with the ThreeTec ZE9 at a similar extrusion temperature of 105 °C/ 100 rpm had
a lower burst and an even surface morphology. Due to the absence of mixing
elements in ram-extrusion processes, the syringe-die method had a poor drug
incorporation and thus a high burst release. Nevertheless, drug release phases
from implants prepared with the syringe-die method were comparable to those of
implants prepared with the ThreeTec ZE9, making it an attractive tool for
formulation screening due to low processing times, small amounts of formulation
blends needed, and the comparability to implants prepared with the ThreeTec
ZE9. Therefore, the syringe-die method as a screening tool for hot-melt extruded
implants was utilized.
For the establishment of an applicability map the influence on dexamethasone
release from PLGA-based implants was investigated in terms of PLGA end
groups, PLGA lactic acid to glycolic acid (L:G) ratio, polymer’s average molecular
weight, and drug loading. Dexamethasone release from implants
follows the typical drug release curve of PLGA-based drug delivery systems
(DDS). A small burst release from excess drug on the implant’s surface, followed
by a lag phase and the release phase, which is designated to the start of polymer
degradation. Lag phases of dexamethasone release from implants prepared with
502H, 503H, and 502 were independent of the drug loading, while lag phases for
dexamethasone release from 752S implants were influenced by drug loading. The
release time after the lag phase was shorter for 752S implants containing higher
drug loadings. Plotting the release phase over the lag phase, dexamethasone
release was visualized in an applicability map. This applicability map was
successfully utilized to develop a biodegradable dexamethasone implant with a
desired release consisting of a lag phase of maximum 7 days and a release phase
of approximately 14 days. This could be achieved by the preparation of a
dexamethasone implant with 50%/ 60% drug loading and a PLGA mixture of
502H/ 502 in a 3:1 ratio.
Next, a formulation of a biodegradable implant for the application of brimonidine
base was developed. The requirement for the implant was that it released the
active substance to the same extend as dexamethasone was released from the
already developed implant in order to possibly enable a simultaneous injection.
Brimonidine release from biodegradable PLGA implants was investigated in terms
of PLGA end groups, polymer molecular weight, L:G ratio, and drug loading.
Release data was again collected in an applicability map, containing lag phase
plotted against release phase, to develop the desired release implant as
previously with dexamethasone implants. However, a biodegradable implant was
successfully developed that released brimonidine from PLGA implants with a 1:1
mixture of 752S/ 503H with a 3-day longer lag phase and almost the same release
time compared to the developed dexamethasone implant.
Combination implants with both drugs released brimonidine within several days,
but dexamethasone release was incomplete for all formulations. Since
simultaneous release from single dexamethasone and brimonidine implants was
complete for both drugs, a drug – drug or drug – drug – PLGA interaction was
assumed but not further investigated. Nevertheless, a combination implant
containing both drugs could be possible using alternative preparation methods
like co-extrusion.
In order to achieve a reliable release test method to obtain drug release curves
from biodegradable implants after a short time period, an accelerated release test
method was established by investigating the influence of temperature and pH of
106
the release medium on dexamethasone release from PLGA implants. The change
of the release medium from aqueous sodium chloride (0.9%, saline) to phosphate
buffered saline pH 2 (PBS, USP) did not accelerate PLGA degradation and thus
dexamethasone release from the implants. The use of PBS pH 12 (USP) provides
an accelerated PLGA degradation through basic catalyzed hydrolysis. PLGA
implants degraded completely at temperatures of 37 °C, 45 °C, and 65 °C.
Unfortunately, lag phases of dexamethasone release could not be observed at
pH 12 due to the rapid PLGA degradation. This makes it difficult to compare
different formulations or estimate drug releases under standard release test
conditions. The best conditions for accelerated release tests of dexamethasone
implants herein were at an elevated temperature of 45 °C in the standard release
medium, saline. By increasing the temperature at release tests, dexamethasone
release from PLGA implants took only half the time of drug release at 37 °C while
still be able to observe differences between the formulations.
Dexamethasone release from 502H/ 502 implants was investigated in terms of
implant sterilization by gamma irradiation and storage time at room temperature
in a silica gel desiccator. The storage time of 2 years for implants prepared with
the ThreeTec ZE9 resulted in a slight dexamethasone release during the lag
phase but was declared as acceptable since the drug release was still similar to
those of implants directly after HME. Dexamethasone release from implants
prepared with the Haake MiniLab Compounder significantly changed after
3 years of storage. Although the typical sigmoidal release curve was still seen, the
burst release increased, dexamethasone was released during the lag phase, and
finally the release phase was decreased. Overall, a 2-years storage of gamma
irradiated, PLGA-based dexamethasone implants was acceptable when it comes
to drug release.
Ultimately, the mechanical properties of biodegradable PLGA implants were
investigated in terms of drug loading, molecular weight of polymer matrix, implant
dimensions such as length and diameter and moisture content. It was possible to
measure and characterize the mechanical properties of biodegradable PLGA
implants with a texture analyzer in terms of drug loading, polymer molecular
weight, implant dimensions and moisture content by implementing an easy-to-use
three-point bending test method. Especially peak forces, but also elongations,
and AUC are sufficient parameters to describe differences in formulation
properties while the slope of the curves have no beneficial correlations in terms
of molecular weight and length of PLGA implants. Without the necessity of a
complex method setup or converting measured parameters into tensile strengths,
this method could be a simple alternative for the quality control of biodegradable
implant formulations.
en
